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The Journal of Immunology, 1999, 162: 5662-5665.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Requirement of Class I Signal Sequence-Derived Peptides for HLA-E Recognition by a Mouse Cytotoxic T Cell Clone1

Silvia Martinozzi2,*, Rita Pacasova2,*, Henri-Jean Boulouis*, Matthias Ulbrecht{dagger}, Elisabeth H. Weiss{dagger}, François Sigaux* and Marika Pla3,*

* Mouse Immunogenetics, Institut National de la Santé et de la Recherche Médicale, Unite 462, Institute of Hematology, Hôpital Saint-Louis, Paris, France; {dagger} Institut für Anthropologie und Humangenetik, Ludwig Maximilians-Universität, Munich, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The human nonclassical MHC class I molecule HLA-E has recently been shown to act as a major ligand for NK cell inhibitory receptors. Using HLA-E-expressing transgenic mice, we produced a cytotoxic T cell clone that specifically recognizes the HLA-E molecule. We report here that this T cell clone lyses HLA-E-transfected RMA-S target cells sensitized with synthetic class I signal sequence nonamers. Moreover, this T cell clone lyses human EBV-infected B lymphocytes, PHA blasts, and PBL, formally demonstrating the surface expression of HLA-E/class I signal-derived peptide complex on human cells. Furthermore, these data show that HLA-E complexed with class I signal sequence-derived peptides is not only a ligand for NK cell inhibitory receptors, but can also trigger cytotoxic T cells (CTL).


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The HLA-E Ag has recently aroused considerable interest in the scientific community. In vitro studies have shown that HLA-E preferentially binds a peptide derived from amino acid residues 3–11 of the signal sequences of most HLA-A, -B, -C, and -G molecules (1, 2, 3, 4). Recent in vitro studies have revealed that HLA-E molecules function as ligands for NK cell inhibitory receptors (5, 6, 7, 8) and that the recruitment of HLA-E on the surface of transfected cells by the addition of class I signal sequence-derived peptides is enough to protect target cells from lysis by NK cell clones (6, 7, 8, 9).

Until recently (8, 10), the lack of HLA-E-specific reagents rendered in vivo study of HLA-E cell-surface expression impossible; the only data available concerning HLA-E cell-surface expression were obtained using human (class Ia-defective) transfectants (3) or mouse cells transfected with HLA-E genes (11). To facilitate the production of such reagents, we generated transgenic mice (TGM)4 that express HLA-E, for which we have included a human ß2-microglobulin transgene (M) to optimize expression of HLA-E on the cell surface. All lymphocytes from double TGM (EM-TGM) were stained (12) with a mAb (B9.12.1) that binds to a monomorphic determinant on all human MHC class I molecules, including HLA-E (13). While the level of HLA-E expressed was rather low compared with that of endogenous (H-2) class I molecules, the HLA-E transgene product possesses all functional properties of a class I molecule (14). This was shown by the induction of both Abs (10) and cytotoxic T cells, and by the rejection of skin grafts from HLA-E-expressing TGM. We have also reported that a significant portion of the mouse CTL response involved in the recognition of HLA-E recognizes HLA-E as an intact molecule and not as an HLA-E-derived peptide presented by a mouse MHC molecule. To further our understanding of the recognition of HLA-E by CTL, we have derived a CTL clone (terminator-1 (TER-1)). We report here the description of this clone that specifically recognizes the HLA-E molecule and whether this molecule is naturally expressed (in human cells) or the product of a transfected gene (in mouse cells). We have used synthetic peptides to define the HLA-E-restricted CTL epitope of this clone. Using the TER-1 clone as a highly specific cell probe allowed us to assess the HLA-E cell-surface expression on human cells. Our results demonstrate for the first time that HLA-E is indeed complexed with class I signal sequence-derived peptides on the surface of human lymphoid cells and show that the HLA-E/class I signal sequence-derived peptides complex is not only a ligand for NK cell inhibitory receptors, but can also interact with mouse TCRs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

All mouse strains used in this study were bred and maintained in our own colony. HLA-E heavy chain TGM (E-TGM) were obtained by microinjection of genomic DNA fragments containing the HLA-E (E*01033) gene (12) into the pronucleus of fertilized eggs [(C57BL/6 x SJL) x BALB/c]. Founder mice were mated to mice of an already established C57BL/10 transgenic line expressing human ß2-microglobulin (M-TGM), thereby yielding double TGM carrying both human genes (EM-TGM). To obtain HLA-E transgenic lines expressing H-2b and H-2d haplotypes, the mice were typed for H-2, and EM-TGM carrying H-2b or H-2d were repeatedly backcrossed to C57BL/10 background mice with H-2b (B10) or H-2d (B10.D2) haplotypes. The mice used in the present study originated from line 81. Cell surface expression of HLA-E transgenic molecules and their alloantigenic function have been described elsewhere (14).

In vivo generation of CTL

Recipient mice were injected with 107 irradiated (25 Gy) spleen cells in the hind footpads. After 3 days, cell suspensions were prepared from draining lymph nodes and cells were cultured in vitro for four more days in the absence of any stimulating cells in culture medium containing Con A-stimulated rat spleen cell supernatant as a lymphokine source (50 U IL-2/ml). The culture medium was MEM {alpha}-medium (Life Technologies, Gaithersburg, MD) supplemented with 100 U/ml penicillin (Life Technologies), 2 mM glutamine (Life Technologies), 5 x 10-5 M 2-ME (Sigma, St. Louis, MO) and 10% heat-inactivated FCS (Life Technologies).

CTL clones

A CTL clone (TER-1) was isolated by limiting dilution from in vivo-induced CTL and maintained in culture by periodic (every 11 days) stimulation. For this 0.5 x 106 CTL were mixed with 10 x 106 irradiated spleen cells originating from TGM expressing HLA-E molecules in a final volume of 10 ml IL-2-containing culture medium (described above). Five days after stimulation the surviving cells were washed and cultured (106 cells) for a further 6 days in 10 ml IL-2-containing culture medium. Cells were used for functional assays 5 days after their last stimulation.

Cell-mediated lympholysis assay

Five thousand 51Cr-labeled target cells were incubated with effector cells at various E:T ratios in round-bottom wells for 4 h. The percentage of specific 51Cr release was calculated as (experimental - spontaneous release)/(maximum - spontaneous release) x 100.

Peptide-induced stabilization of HLA-E molecules

RMA-S cells transfected with human ß2-microglobulin and HLA-E heavy chain genes were cultured at 26°C for 18 h. Saturating amounts of peptides (Eurogentec, Brussels, Belgium) were added to the culture to a final concentration of 25 µM (class I leader) or 100 µM (BZLF-1) peptides and incubated at 37°C for 1 h.

Flow cytometry

Cells (2 x 105) were successively incubated with saturating concentrations of mAb and FITC-conjugated goat F(ab')2 anti-mouse Ig. Both incubations were conducted on ice for 30 min, followed by two washing steps. Cytofluorometry was conducted on a FACScan and analyzed with Cell Quest software (Becton Dickinson, San Jose, CA).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To characterize primary in vivo-induced anti-HLA-E CTL, and especially those involved in graft rejection, we have used an in vivo approach based on our previous observations (15) that injection of allogeneic cells into the hind footpads leads to the development of CTL within the draining lymph nodes. Spleen cells from double EM-TGM carrying H-2b haplotypes were injected into the hind footpads of nontransgenic H-2-compatible mice. After 3 days, cell suspensions were prepared from draining lymph nodes and cells were cultured for four more days in the absence of any stimulating cells. After this period, required to allow full differentiation of sensitized CTL precursors (16), lymph node cells were tested for the presence of CTL in a 51Cr-release assay, using Con A blasts as target cells (Fig. 1GoA). CTL generated in this way lysed Con A blasts from both H-2b and H-2d EM-TGM, indicating that the elicited CTL recognized HLA-E as an intact molecule and not as an HLA-E-derived peptide presented by a mouse MHC molecule. No lysis of target cells that originated from M-TGM was observed. A CTL clone (TER-1) was derived by limiting dilution and maintained by periodic stimulation with irradiated H-2b EM-TGM spleen cells. The TER-1 clone was found to be cytotoxic (Fig. 1GoB) for target cells from both H-2-matched (H-2b) and H-2-mismatched (H-2d) EM-TGM, but not from M-TGM. The results (Fig. 1GoB) revealed very efficient killing (65% at an E:T ratio of 0.6:1) of HLA-E-positive targets. To further characterize its specificity, the TER-1 clone was tested on mouse fibroblasts (H-2k) expressing various HLA class I molecules (-A3, -A11, -A26, -A29, -B7, -B27, -Cw3, and -Cw7) or on P815 cells (H-2d) expressing HLA-A2 molecules. A FACS analysis was performed using the HLA class I-reactive mAb (B9.12.1), which confirmed the cell-surface expression of HLA class I molecules on these mouse transfectants (data not shown). Kk- and Ld-reactive CTL (Fig. 2Go) were used as positive controls for target cell lysis. None of the transfectants was lysed by the TER-1 clone (Fig. 2Go), indicating that this clone did not recognize any of the HLA class I molecules tested.



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  		FIGURE 1. Anti-HLA-E cytotoxic T cell response elicited in mice. Anti-HLA-E cytotoxic activity was evaluated by a 4-h 51Cr release assay using as targets Con A blasts from TGM expressing HLA-E molecules (EM; full symbols) or only human ß2-microglobulin (M; empty symbols) carrying H-2b (bb), H-2d (dd), or H-2b/H-2d (bd) haplotypes. A, Primary in vivo induction of HLA-E-reactive cytotoxic T cells in mice of the H-2b haplotype immunized with H-2-matched spleen cells expressing HLA-E molecules (see Materials and Methods). B, Lysis of HLA-E-expressing mouse target cells by the TER-1 CTL clone.

 


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  		FIGURE 2. Classical HLA class I molecules are not recognized by the TER-1 clone. Cytotoxic reactivity of the TER-1 clone (solid lines) was tested in a 4-h 51Cr-release assay using as targets either mouse fibroblasts (H-2k) expressing various HLA class I molecules (-A3, -A11, -A26, -A29, -B7, -B27, -Cw3, and -Cw7) or P815 cells (H-2d) expressing HLA-A2 molecules. HLA-E-expressing target cells (x) were used as a positive control for TER-1 cytotoxic activity. Kk- and Ld-reactive CTL (dotted lines) were used as positive controls for target cell lysis.

 
Synthetic peptides were then used to sensitize Tap-defective RMA-S target cells transfected with HLA-E (E*01033) and human ß2-microglobulin genes, thereby defining the epitope recognized by the TCR of the TER-1 clone. As expected, synthetic nonamers derived from residues 3–11 of the signal sequences of HLA-A2 (VMAPRTLVL), -A3 (VMAPRTLLL), -B7 (VMAPRTVLL), and H-2Db (AMAPRTLLL) bound to HLA-E molecules, resulting in increased expression of HLA-E on the surface of the processing-defective RMA-S mutant (Fig. 3GoA), and sensitized RMA-S cells to lysis by the TER-1 clone (Fig. 3GoB). HLA-E cell-surface expression on RMA-S transfectants could also be enhanced by adding the BZLF-139–47 (SQAPLPCVL) nonamer derived from the EBV protein BZLF-1 (Fig. 3GoA). However, HLA-E complexed with the BZLF-139–47 peptide was not recognized by the TER-1 clone. These results indicate that TER-1 cells bearing an {alpha}ß receptor (data not shown) specifically recognize HLA-E gene products complexed with MHC class I signal sequence-derived peptides.



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  		FIGURE 3. Recognition by the TER-1 clone of HLA-E molecules stabilized by class I signal sequence-derived peptides. RMA-S cells transfected with human ß2-microglobulin and HLA-E heavy chain genes were incubated for 1 h at 37°C in the absence (No Pept.) or presence of saturating amounts of synthetic nonamers derived from residues 3–11 of the signal sequences of HLA-A2 (VMAPRTLVL, pLA2), -A3 (VMAPRTLLL, pLA3), -B7 (VMAPRTVLL, pLB7), and H-2Db (AMAPRTLLL, pLDb), or the BZLF-139–47 nonamer (SQAPLPCVL, BZLF-1) derived from the EBV protein BZLF-1. A, Enhancement of cell-surface expression of HLA-E molecules on RMA-S transfectants exposed to various peptides. Specific indirect fluorescence profiles (full traces) obtained with HLA-E-reactive B9.12.1 mAb were compared with background staining fluorescence profiles of RMA-S transfectants incubated only with FITC-conjugated goat F(ab')2 anti-mouse Ig (dotted traces). B, Lysis by the TER-1 clone of RMA-S transfectants that were exposed to class I signal sequence-derived peptides. Cytotoxic reactivity of the TER-1 clone was tested in a 4-h 51Cr release assay.

 
We used the TER-1 clone as a very potent and highly specific cell probe to check for HLA-E cell-surface expression on human cells. We tested the TER-1 clone on a panel of EBV-transformed human B lymphocytes, all of which express the HLA-A3, -B7, and -Cw7 class I molecules that we have shown not to be recognized by this clone (Fig. 2Go). The HLA-E-reactive TER-1 clone efficiently lysed all human EBV line cells (Fig. 4GoA). No significant lysis was observed with HLA class I-negative cells (K562). The TER-1 clone was further tested on human PBL and on PHA blasts originating from two healthy donors, #298 (HLA-A2, 3; B7; Cw7) and #573 (HLA-A2; B7; Cw7). We show (Fig. 2Go) that classical class I molecules expressed on these targets were not recognized by the TER-1 clone. Efficient lysis of human cells was observed, with the exception of HLA class I-negative ones (Daudi; Fig. 4GoB). The addition of W6/32 mAbs, which recognize both classical and nonclassical class I heavy chains associated with ß2-microglobulin, including the HLA-E product (3), or the addition of mAbs, which recognize the {alpha}ß TCR, efficiently inhibited lysis of human and mouse targets (data not shown).



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  		FIGURE 4. Lysis of human lymphocytes by the class I signal sequence-derived peptide-specific HLA-E-restricted T cell clone, TER-1. Cytotoxic reactivity of the TER-1 clone was tested in a 4-h 51Cr release assay on human homozygous (HLA-A3; B7; Cw7) EBV cell lines (BM14, EA, HHKB, and SCHU, A), on human PBMC (full lines, B), and on PHA blasts (dotted lines, B), both originating from two healthy donors (#298: HLA-A2, 3; B7; Cw7, and #573: HLA-A2; B7; Cw7), and on HLA class I-negative cells (K562, A; and Daudi, B).

 
The results of HLA-E peptide-binding and cytotoxic assays conducted in mice, combined with the results of cytotoxic assays of human cells (Fig. 4Go), using the class I signal sequence-derived peptide-specific HLA-E-restricted T cell clone, provide proof of in vivo HLA-E cell-surface expression by lymphoid cells in man. Moreover, these results show that at least a significant portion of HLA-E molecules bear peptides derived from appropriate class I leader sequences. The allelic variation of the HLA-E polypeptide that has been described among caucasians (17) affects only amino acid position 107, which is occupied either by G (HLA-EG) or R (HLA-ER). All the EBV homozygous cell lines mentioned in Fig. 4GoA except the EA line have G at position 107. The HLA-E-reactive TER-1 clone equally lysed human cells carrying the HLA-EG or the HLA-ER alleles, indicating that HLA-E-allelic changes at position 107 did not affect recognition by this clone. These results suggest that both alleles present in caucasians can be expressed on the cell surface as HLA-E polypeptides complexed with class I signal sequence-derived peptides.

Our studies using CTL generated in mice show that HLA-E refolded around peptides derived from residues 3–11 of MHC class I molecule signal sequences mediates cognate recognition events by specific interactions not only with NK cell receptors, but also with the TCR of CTL. In the human, a soluble tetrameric form of HLA-E was shown (6) to bind to NK cells as well as to a small subset (mean 1.7%) of peripheral blood CD3+ T cells. Binding of the HLA-E tetramer to NK cells is abolished by mAbs that recognize CD94 (6), which is an NK cell receptor, indicating interaction between this receptor and HLA-E. However no data are available regarding identification of the HLA-E tetramer-binding receptor on T cells. The crystal structure of HLA-E was determined in complex with a prototypic ligand derived from highly conserved residues of the human MHC class I leader sequence (4), indicating that the basic architectural structure of HLA-E is similar to that of classical MHC class I molecules. In particular, the structural features required for interaction with the CD8 receptor are all conserved, implying that HLA-E may be capable of binding this receptor (4). In mice, the HLA-E homologue Qa-1 can interact with the {alpha}ß TCR (18, 19, 20). Our results (Fig. 3GoA), as well as those of Ulbrecht et al. (21), demonstrate that peptides derived from viral proteins bind to HLA-E in vitro. Using HLA-E-expressing TGM, we are currently investigating whether HLA-E might play a role as a restriction element for viral proteins in vivo. The exact role of HLA-E in immunological recognition and regulation is still pending. EM-TGM are not only a reliable source of cells expressing HLA-E molecules, but also provide a means to investigate the biological function of HLA-E molecules in vivo.


   Acknowledgments
 
We thank Dr. Bernard Frangoulis for critical reading of the manuscript, and Martine Chopin for organizing the breeding of transgenic lines. M.P. thanks Dr. Pavol Ivanyi for his continuous encouragement and helpful and provocative discussions.


   Footnotes
 
1 This work was supported by institutional grants from Institut National de la Santé et de la Recherche Médicale and in part by research grants from La Ligue Contre le Cancer and from the Association Recherche et Transfusion. S.M. is a recipient of a Marie Curie Research Training Grant. Back

2 S.M. and R.P. contributed equally to this work. Back

3 Address correspondence and reprint requests to Dr. Marika Pla, Mouse Immunogenetics, Institut National de la Santé et de la Recherche Médicale Unite 462, Institute of Hematology, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France. E-mail address: Back

4 Abbreviations used in this paper: TGM, transgenic mouse/mice; E-TGM, HLA-E heavy chain TGM; M-TGM, ß2-microglobulin TGM; EM-TGM, HLA-E heavy chain and ß2-microglobulin TGM; TER-1, terminator-1. Back

Received for publication December 1, 1998. Accepted for publication March 9, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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